Project Summary/Abstract Tuberculosis (TB) is the single greatest infectious disease killer globally. Multidrug-resistant (MDR) TB, caused by M. tuberculosis resistant to isoniazid and rifampin, threatens global TB control. The lengthy, expensive treatments that can cure MDR-TB are often not accessible by patients who need them, are only 50% successful, and cause unacceptably high toxicity. Rifampin, by virtue of its sterilizing activity against M. tuberculosis, plays an indispensable role in modern six-month `short-course' therapy for drug-susceptible TB. In MDR-TB, it is the infecting bacteria's resistance to rifampin that is primarily responsible for the prolonged treatment duration of 18-24 months that is required when rifampin cannot be used. Up to now, there are simply no anti-TB drugs with demonstrated sterilizing potency equivalent to that of rifampin. Strategies that restore rifampin activity, even partially, may have important treatment shortening effects for MDR-TB. Strategies to potentiate rifampin activity -- that is, to increase the antituberculosis effect of a given dose of rifampin -- may also be relevant for treatment of drug-susceptible TB. Lamichhane and colleagues at Johns Hopkins University recently showed that the combination of rifampin plus a carbapenem/?- lactamase inhibitor is synergistic and lowers the effective rifampin MIC, even restoring the activity of rifampin in vitro against rifampin-resistant M. tuberculosis. Further, the combination of meropenem plus amoxicillin/clavulanate has potent antituberculosis activity in human TB and is safe and well-tolerated. We propose a focused, proof-of-concept clinical trial to determine whether, in pulmonary TB patients, a carbapenem/ ?-lactamase inhibitor combination can serve as a rifampin `sensitizer' and thereby potentiate the antituberculosis activity of rifampin. In this phase 2a randomized, open-label trial we will enroll patients with rifampin-susceptible pulmonary TB as well as patients with rifampin-resistant pulmonary TB. Participants will be randomized to receive one of 5 treatments for 7 days: Baseline DST Regimen Regimen Components Rifampin resistant Randomized (1:1) to: A Rifampin Meropenem Amx/Clv B - Meropenem Amx/Clv Rifampin susceptible Randomized (1:1:1) to: C Rifampin Meropenem Amx/Clv D - Meropenem Amx/Clv E Rifampin - - Abbreviations: DST, drug-susceptibility testing; Amx/Clv, amoxicillin/clavulanate The primary endpoint is mean daily fall in log10 colony forming units of M. tuberculosis per mL of sputum over 7 days of treatment. Safety of the regimens will be assessed. We will incorporate intensive pharmacokinetic (PK) and mycobacteriology assessments which, in the context of a range of M. tuberculosis minimum inhibitor concentrations (MICs) and expected inter-individual rifampin PK variability, will allow determination of the pharmacodynamic relationships between rifampin, rifampin area under the concentration-time curve (AUC), and antituberculosis activity when rifampin is administered in combination with meropenem and amoxicillin/clavulanate. The ability to recoup rifampin's antituberculosis activity, even partially, through combination with a carbapenem and ?-lactamase inhibitor would transform the treatment of MDR-TB and have implications for individual patients and public health. Potentiation of rifampin activity is also likely to be relevant for treatment of drug-susceptible TB, not only in certain patient sub-groups but also as a component of a treatment-shortening strategy applicable to the majority of TB patients worldwide.